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Blood-brain barrier pathology in cerebral small vessel disease

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Neural Regeneration Research 2024年第6期19卷 1233-1240页

作者： Ruxue Jia Gemma Solé-Guardia Amanda J.Kiliaan department of Medical Imaging AnatomyRadboud University Medical CenterDonders Institute for BrainCognition&BehaviorCenter for Medical NeurosciencePreclinical Imaging Center PRIMERadboud Alzheimer CenterNijmegenthe Netherlands

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the *** at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of *** signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease *** pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier ***,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel ***,the purpose of this review is to provide a new foundation in the study of small vessel disease ***,we discuss the main structural domains and functions of the blood-brain ***,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel ***,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

关键词： blood-brain barrier dysfunction cerebral blood flow cerebral hypoperfusion endothelial dysfunction hypertension inflammation magnetic resonance imaging neurovascular unit oxidative stress small vessel disease tight junctions transcytosis

Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

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Cellular & Molecular immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen Tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang Chen department of Cell Biology of National Translational Science center for Molecular Medicine and department of Clinical immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of Medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell ***,the role of Id2 in CD8^(+)T-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm *** deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification immune evasion

Progress and challenges for replacing n-methyl-2-pyrrolidone/polyvinylidene fluoride slurry formulations in lithium-ion battery cathodes

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Progress in Natural Science:Materials International 2024年第01期34卷 194-206页

作者： Sung Cik Mun Yeong Hoon Jeon Jong Ho Won Battery Materials Research center LG Chem department of Energy Engineering Dankook University

With electric vehicles, energy storage systems, and portable electronic devices becoming increasingly popular, the demand for lithium-ion batteries has surged considerably. In the lithium-ion battery industry, n-methyl-2-pyrrolidone(NMP) is widely used as the solvent for cathode slurry, and polyvinylidene fluoride(PVDF) is used as the cathode binder. However, because of the harmful effect of NMP on the environment and human health, the use of NMP and PVDF for lithium-ion batteries will be highly regulated in the future. Therefore, developing eco-friendly alternatives is crucial for formulating systems using new solvents and binders. Despite numerous efforts, these alternatives have not been widely adopted across the lithium-ion battery industry. It is due to their limited ability to compete on price or performance to replace the traditional NMP/PVDF slurry formulations. This review investigates developments in the search for new solvents and binders that can be used in cathode slurry compositions. The new systems can potentially decrease energy consumption and manufacturing costs associated with NMP recovery, energy-intensive drying processes, and material expenses. We discuss key factors and technical challenges from earlier studies and compare them with the current, optimized formulations based on NMP and PVDF.

关键词： Lithium-ion battery Eco-friendly alternative Slurry formulation Chemical regulation Binder performance

Trends in oxycodone and oxycodone-containing analgesics administration for back pain in emergency departments in the USA(2007–2018)

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World Journal of Emergency Medicine 2024年第3期15卷 169-174页

作者： Jonathan Chabon Jemer Garrido Deanna Schreiber-Gregory Jefferson Drapkin Sergey Motov department of Emergency Medicine Maimonides Medical CenterBrooklyn 11219USA

BACKGROUND:To describe trends in oxycodone and oxycodone-containing analgesic prescribing for the treatment of back pain among adults in emergency departments(EDs) in the USA from 2007 to ***:Data were gathered from the National Hospital Ambulatory Medical Care Survey(NHAMCS) from 2007 to *** study population included individuals of all ages presenting to USA *** NHAMCS reasons for visit and oxycodone drug ID codes were used to isolate patients with back *** main outcome was the proportion of oxycodone and oxycodone-containing analgesics prescribed for back pain in the EDs over the specified time ***:There was a relative decrease in the overall administration of oxycodone for back pain in the EDs by 62.3% from 2007(244,000 visits) to 2018(92,000 visits).The proportion of ED patients prescribed with oxycodone-containing analgesics for back pain increased among patients aged 45 years and older(from 43.8% to 57.6%),female patients(from 54.5% to 62.0%),black patients(from 22.5% to 30.4%),and Hispanic/Latino patients(from 9.4% to 19.6%).Oxycodone/acetaminophen was most prescribed and accounted for 90.2% of all oxycodone-containing analgesics in 2007,with a decrease to 68.5% in *** oxycodone was the second most prescribed medication,accounting for 6.1% in 2007 and 31.5% in ***:The overall number of oxycodone-containing analgesics decreased significantly from 2007 to ***,that number trended upward in 45-year-old and older,female,black,or Hispanic/Latino patients from 2007 to *** total amount of pure oxycodone increased significantly from 2007 to 2008.

关键词： Oxycodone Back pain Emergency department

Global Stability to Steady Supersonic Rayleigh Flows in One-Dimensional Duct

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Chinese Annals of Mathematics,Series B 2024年第2期45卷 279-296页

作者： Fenglun WEI Jianli LIU department of Mathematics Shanghai University Newtouch center for Mathematics of Shanghai University

Heat exchange plays an important role in hydrodynamical systems,which is an interesting topic in theory and *** this paper,the authors consider the global stability of steady supersonic Rayleigh flows for the one-dimensional compressible Euler equations with heat exchange,under the small perturbations of initial and boundary conditions in a finite rectilinear duct.

关键词： Compressible Euler equations Heat exchange Supersonic Rayleigh fow Steady solution Classical solution

Unlocking T cell exhaustion:Insights and implications for CAR-T cell therapy

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3416-3431页

作者： Dian Xiong Haijun Yu Zhi-Jun Sun State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of EducationHubei Key Laboratory of StomatologySchool&Hospital of StomatologyFrontier Science Center for Immunology and MetabolismTaikang Center for Life and Medical ScienceWuhan UniversityWuhan 430079China department of Radiation and Medical Oncology Hubei Province Cancer Clinical Study CenterHubei Key Laboratory of Tumor Biological BehaviorsZhongnan Hospital of Wuhan UniversityWuhan 430071China

Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen(BCMA)for hematological malignancies,albeit with moderate outcomes in solid ***,despite these advancements,the efficacy of CAR-T therapy is often compromised by T cell exhaustion,a phenomenon that impedes the persistence and effector function of CAR-T cells,leading to a relapse rate of up to 75%in patients treated with CD19 or CD22 CAR-T cells for hematological *** to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing *** this review,we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell *** insights,combined with lessons learned from benchmarking CAR-T based products in recent clinical trials,aim to address the challenges posed by T cell exhaustion,potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.

关键词： Cancer immunotherapy CAR-T therapy T cell exhaustion Tumor immune microenvironment Spatial immune contexture Single-cell technologies CAR-T engineering Combination therapy

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

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Cellular & Molecular immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong Lamao Meichao Gu Xuanxuan Jin Ying Liu Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao Thomas S.Fulford Adam P.Uldrich Catherine C.L Wong Wensheng Wei Biomedical Pioneering Innovation center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina center for Precision Medicine Multi-Omics Research Peking University Health Science CenterPeking University100191BeijingChina department of Microbiology and immunology at the Peter Doherty Institute for Infection and immunity The University of MelbourneParkvilleVIC3010Australia Cancer immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key Laboratory for Complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate *** our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer *** found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T *** coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX ***,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer *** our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T ***,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell Cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite immunotherapy

Cancer immunotherapy with envelopedself-amplifying mRNA CARG-2020 thatmodulates IL-12,IL-17 and PD-L1 pathways toprevent tumor recurrence

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Acta Pharmaceutica Sinica B 2024年第1期14卷 335-349页

作者： Ju Chen Bhaskara Reddy Madina Elham Ahmadi Timur Olegovich Yarovinsky Marie Marthe Krady Eileen Victoria Meehan Isabella China Wang Xiaoyang Ye Elise Pitmon Xian-Yong Ma Bijan Almassian Valerian Nakaar Kepeng Wang department of immunology School of MedicineUniversity of Connecticut Health CenterFarmingtonCT 06030USA CaroGen Corporation FarmingtonCT 06030USA The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine Foshan Hospital of Traditional Chinese MedicineFoshan 528000China The Loomis Chaffee School WindsorCT 06095USA

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for ***,we describe the application of virus-like vesicles(VLV)for delivery of three immunomodulators alone and in combination,as a promising approach for cancer *** vectors were designed to deliver single chain interleukin(IL)-12,shorthairpin RNA(shRNA)targeting programmed death ligand 1(PD-L1),and a dominant-negative form of IL-17 receptor A(dn-IL17RA)as a single payload or as a combination *** delivery of the VLV vector expressing IL-12 alone,as well as the trivalent vector(designated CARG-2020)eradicated large established ***,only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice,indicating a benefit of the combined *** abscopal effects of CARG-2020 on the non-injected contralateral tumors,as well as protection from the tumor cell re-challenge,suggest immune-mediated mechanism of protection and establishment of immunological ***,CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting *** ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

关键词： Virus-like vesicles Oncolytic virus IL-12 IL-17 PD-L1 T cell exhaustion Combination therapy Cancer immunotherapy

Current understanding of ELF4 deficiency:a novel inborn error of immunity

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World Journal of Pediatrics 2024年第5期20卷 444-450页

作者： Hong-Qiang Du Xiao-Dong Zhao department of Rheumatology&immunology National Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Child Rare Diseases in Infection and ImmunityChildren’s Hospital of Chongqing Medical UniversityZhongshan Er Road 136Yuzhong DistrictChongqingChina

Background ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity(IEIs),specifically categorized as a“disease of immune dysregulation.”Cases of this condition,reported by our team and others,are very limited *** such,our current knowledge of this new disease remains *** review aims to provide a brief overview of the clinical manifestations,pathogenesis,and treatment strategies for this novel *** sources A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 *** search strategy was“ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor”as of the time of manuscript *** The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer,abdominal pain,and diarrhea in pediatric *** some cases,immunodeficiency and autoimmunity can also be *** Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 *** blotting for ELF4 expression of the patient’s cells can confirm the pathogenic effect of the *** fully confirm the pathogenicity of the variant,further functional test is strongly *** and biologics are the mainstream management of ELF4 deficiency *** Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of *** atypical presentations are prominent,variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 *** of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.

关键词： ELF4 transcription factor immune dysregulation Inborn errors of immunity Mechanism Recurrent infections